ONT-380/T-DM1 Combo Shows Promise in HER2+ Breast Cancer With CNS Mets

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Erika P. Hamilton, MD, discusses the significance of these trials and the impact ONT-380 may have on the treatment paradigm of HER2-positive breast cancer.

Erika P. Hamilton, MD

The combination of the oral HER2 inhibitor ONT-380 and T-DM1 (ado-trastuzumab emtansine; Kadcyla) has shown early evidence of clinical activity in patients with metastatic HER2-positive breast cancer with or without brain metastases, according to results of a phase Ib study.1

In the dose-escalation study, which was presented during the 2015 San Antonio Breast Cancer Symposium, patients with HER2-positive disease with or without brain metastases received ONT-380 combined with a 3-week treatment of T-DM1 at 3.6 mg/kg.

Results showed that, out of the 51 patients enrolled, the maximum tolerated dose was 300 mg twice daily, with 14% of patients having dose-limiting toxicities, including an elevation of liver enzymes (AST/ALT). Grade 1/2 events included vomiting and diarrhea. At the 350-mg dose, 43% of patients had dose-limiting toxicities, including grade 3 vomiting, hypersensitivity, and fatigue.

In 33 of 43 evaluable patients, the best systemic response, regardless of dose, was 11 partial responses, 16 patients with stable disease, and 6 with progressive disease. The clinical benefit rate was 58%.

Results of a second study,2 also presented during the meeting, specifically looked at the patients with brain metastases (n = 24) from the phase Ib research who received ONT-380 in combination with T-DM1, capecitabine, trastuzumab, or capecitabine and trastuzumab.

In the 14 evaluable patients who received one of the ONT-380 combinations, responses included 1 complete response (T-DM1), 4 partial responses (T-DM1, n = 2; trastuzumab + capecitabine, n = 1; capecitabine, n = 1), and 9 patients with stable disease (T-DM1, n = 5; trastuzumab, n = 3; trastuzumab + capecitabine, n = 1).

These findings demonstrate early clinical activity of ONT-380 with T-DM1 against HER2-positive disease with brain metastases.

OncLive: Can you give an overview of both studies examining ONT-380?

In an interview with OncLive, Erika P. Hamilton, MD, the director of Breast Cancer and Gynecologic Research Program at Sarah Cannon Research Institute and an author on both studies, discusses the significance of these trials and the impact ONT-380 may have on the treatment paradigm of HER2-positive breast cancer.Hamilton: This is a novel HER2-specific inhibitor called ONT-380 made by a company named Oncothyreon. What is special about this drug is it is HER2-specific.

Most of our oral HER2 inhibitors block not only HER2, but also other proteins such as EGFR. Often, that is what translates to a lot of the toxicities, such as rash and diarrhea. What is special about this medicine is that it only blocks HER2, so it tends to be very tolerable in the patients who have had it thus far.

Additionally, it crosses into the blood-brain barrier. As we all know, brain metastases are a special problem for HER2-positive patients; up to 50% of HER2-positive patients will end up with brain metastases. This is much higher than patients with triple-negative or estrogen receptor¬—positive breast cancer.

The first study is an update with the T-DM1 combination with ONT-380. This is kind of in the second-line setting of HER2-positive metastatic breast cancer. The response rate is 41% in that, which is pretty encouraging. Not only are women responding, but also they are remaining on treatment for a long time. The clinical benefit rate is 59% in that study.

The second study is a combination of all of the women who have brain metastases from that T-DM1 combination trial. There is also their third-line study, which is capecitabine, trastuzumab and ONT-380.

What is particularly compelling there is how well the women with brain metastases did. The response rates are in the 33% to 38% range, and the clinical benefit is somewhere between 44% and 59%, depending on whether women had received local therapy to their brain lesions.

Are there any overlapping toxicities with the triplet?

Oncothyreon is actually moving this drug into a phase II study. They’re going to take the triplet into trial first: capecitabine and trastuzumab versus capecitabine, trastuzumab, and ONT-380.There really isn’t. I think that’s the really attractive thing about ONT-380. It doesn’t cause the nausea and diarrhea like we see with some of the other medications. With capecitabine, patients can certainly have hand-foot syndrome, but that can be controlled with dose reductions. Capecitabine alone can also cause some diarrhea. Trastuzumab did not add any toxicity to the combination.

What is the current standard of care currently for HER2+ patients with brain mets?

The one thing we did see with the addition of ONT-380 was the elevation in liver enzymes AST/ALT. However, reducing the drug dosage treated it.We don’t have a lot of amazing treatment options. Often, these women get treated with some type of radiation option—whether that’s stereotactic radiosurgery or whole brain radiation.

As far as drug treatments, there are anecdotal reports of T-DM1 crossing the blood-brain barriers as well as pertuzumab (Perjeta). However, whether it is really the fact that they crossed the blood-brain barrier, or whether it is just getting into the brain in women who have brain metastases and the blood-brain barrier is disrupted there, is a little bit unclear. There’s not great data there.

Is there an understanding of why brain metastases are more likely in HER2-positive breast cancer versus other breast cancers?

What are some of the biggest challenges to tackle still with HER2-positive disease?

The standard therapy for later-line patients who have brain metastases is probably capecitabine with lapatinib. Lapatinib is our one drug with pretty good evidence that it gets into the brain, but the response rates of that combination really aren’t that compelling.HER2-positive disease tends to be more aggressive. We know that it tends to spread to the lymph nodes, and be more advanced at the time that we find it. There are multiple reasons that it tends to be more aggressive, and the brain is one of the places that it really likes to go.We are in a really good space right now with HER2-positive disease. We had the approval of pertuzumab in 2012 for metastatic disease and then its later approval in the neoadjuvant setting. Then, we had T-DM1 approved in 2013. Plus, we have the good old favorite of trastuzumab.

What is on the horizon in this setting in HER2+ disease?

I think the challenge now is where these drugs are going to end up for treatment. Right now, the metastatic setting normally comprises chemotherapy combined with pertuzumab and trastuzumab. The second-line setting is really T-DM1, and the third-line setting is pretty open. As T-DM1 and pertuzumab get used more frequently in the neoadjuvant or adjuvant space, I think the metastatic sequence might be up in the air.One of the hot topics right now is immunotherapy. Most of our immunotherapy data in breast cancer is with triple-negative disease. There are more trials coming looking at HER2-positive disease, as well. That is going to be really interesting to see, whether immunotherapy gets into that space in combination with T-DM1, or with pertuzumab. We will probably see immunotherapy in the earlier space, such as neoadjuvant or adjuvant therapy, as well.


  1. Ferrario C, Hamilton E, Aucoin N, et al. A phase 1b study of ONT 380, an oral HER2-specific inhibitor, combined with ado trastuzumab emtansine (T DM1), in HER2+ metastatic breast cancer (MBC). Presented at: 2015 San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract P4-14-20.
  2. Murthy RK K, Hamilton E, Borges VF F, et al. ONT-380 in the treatment of HER2+ breast cancer central nervous system (CNS) metastases (mets). Presented at: 2015 San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX; Abstract P4-14-19.

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